PROJECT ABSTRACT Vector-borne diseases affect millions of people worldwide and are becoming an increasing threat as the effects of climate change become more significant. Due to the rise in global temperatures, the likelihood of vector borne diseases will increase in many areas as the range of insects, such as mosquitos, expands and changes. Wolbachia are maternally transmitted bacteria that infect nearly half of the insect species on the planet and block the replication and transmission of several human pathogens within insect vectors (so called ?pathogen blocking?). Wolbachia-infected mosquitos have been released in several parts of the world in order to control the transmission of Dengue virus. Importantly, the mechanism of pathogen blocking is not well understood. Unfortunately, our understanding of the Wolbachia-vector systems have been limited due to the lack of genetic tools in Wolbachia and the intractability of many important vectors. Our project is aimed at overcoming these obstacles by using the model system, Drosophila melanogaster, to identify genetic factors important for the interaction of Wolbachia with its host and SINV, an RNA virus. Our project uses the powerful genetic tools available in the fly to identify host components necessary for Wolbachia pathogen blocking. Our results will define the genetic interaction network for Wolbachia and key host pathways relevant to RNA virus replication, revealing mechanisms used by the bacterium to block pathogens, allowing for precise experimentation in non-model organisms, such as mosquito vectors. Our innovative approach will serve as a platform to mechanistically investigate the Wolbachia-insect- virus tripartite symbioses. The use of a model system allows us to leverage the power of Drosophila genetics to reveal mechanisms of interaction in a previously intractable intracellular symbiont. Results will be broadly relevant to other disease systems, as we will identify pathways and mechanisms for microbe-vector interaction.